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Degradation, Metabolism and Relaxation Properties of Iron Oxide Particles for Magnetic Resonance Imaging
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Whereas the effect of size and coating material on the pharmacokinetics and biodistribution of iron oxide based contrast agents are well documented, the effect of these parameters on liver metabolism has never been investigated. The primary purpose of this work was to evaluate the effect of iron oxide particle size and coating on the rate of liver clearance and particle degradation using a rat model.

The magnetic and relaxation properties of five different iron oxide contrast agents were determined prior to the onset of the animal studies. The R2* values and the T1-enhancing efficacy of the agents were also evaluated in blood using phantom models. The results of these studies indicated that the efficacy of these agents was matrix and frequency dependent. Correlations between the R2* values and the magnetic properties of the agents were established and a new parameter, Msat/r1, was created to enable better estimations of contrast agent T1-enhancing efficacy in blood.

The bio-distribution of one of the agents was also evaluated to assess the importance of sub-cellular particle distribution, using an isolated rat liver cell model. Phantom models were also used to verify that materials with magnetic properties similar to the particle breakdown products (ferritin/hemosiderin) may induce signal reduction when compartmentalized in a liver cell suspension. The results revealed that the cellular distribution of the agent did not influence the rate of particle degradation. This finding conflicted with current theory. Additionally, the study indicated that the compartmentalization of magnetic materials similar to ferritin may induce significant signal loss.

Methods enabling the accurate determination of contrast agent concentration in the liver were developed and validated using one of the agents. From these measurements the liver half-life of the agent was estimated and compared to the rate of liver clearance, as determined from the evolution of the effective transverse relaxation rate (R2*) in rat liver. The results indicate that the liver R2* enhancement persisted at time points when the concentration of contrast agent present in the liver was below method detection limits. The prolonged R2* enhancement was believed to be a result of the compartmentalisation of the particle breakdown products within the liver cells.

Finally, the liver clearance and degradation rates of the five different iron oxide particles in rat liver were evaluated. The results revealed that for materials with similar iron oxide cores and particle sizes, the rate of liver clearance was affected by the coating material present. Materials with similar coating, but different sizes, exhibited similar rates of liver clearance.

In conclusion, the results of this work strongly suggest that coating material of the iron oxide particles may contribute significantly to the rate of iron oxide particle clearance and degradation in rat liver cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 92
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1362
Keywords [en]
Radiology, Magnetic Resonance Imaging, contrast agents, iron oxide particles, metabolism, relaxation mechanisms
Keywords [sv]
Radiologisk forskning
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-4311ISBN: 91-554-5998-6 (print)OAI: oai:DiVA.org:uu-4311DiVA, id: diva2:164830
Public defence
2004-06-03, Grönwallsalen, Akademiska sjukhuset, Ing. 70, b.v., Uppsala, 13:15
Opponent
Supervisors
Available from: 2004-05-12 Created: 2004-05-12Bibliographically approved
List of papers
1. Characterisation of the relaxation and magnetic properties of five different iron oxide particles: Evaluation of T1-enhancing efficacy
Open this publication in new window or tab >>Characterisation of the relaxation and magnetic properties of five different iron oxide particles: Evaluation of T1-enhancing efficacy
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In: MRMArticle in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-91937 (URN)
Available from: 2004-05-12 Created: 2004-05-12Bibliographically approved
2. Hepatic cellular distribution and degradation of iron oxide nanoparticles following single intravenous injection in rats: implications for magnetic resonance imaging
Open this publication in new window or tab >>Hepatic cellular distribution and degradation of iron oxide nanoparticles following single intravenous injection in rats: implications for magnetic resonance imaging
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2004 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 316, no 3, p. 315-323Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to determine the cellular distribution and degradation in rat liver following intravenous injection of superparamagnetic iron oxide nanoparticles used for magnetic resonance imaging (NC100150 Injection). Relaxometric and spectrophotometric methods were used to determine the concentration of the iron oxide nanoparticles and their degradation products in isolated rat liver parenchymal, endothelial and Kupffer cell fractions. An isolated cell phantom was also constructed to quantify the effect of the degradation products on the loss of MR signal in terms of decreased transverse relaxation times, T2*. The results of this study show that iron oxide nanoparticles found in the NC100150 Injection were taken up and distributed equally in both liver endothelial and Kupffer cells following a single 5 mg Fe/kg body wt. bolus injection in rats. Whereas endothelial and Kupffer cells exhibited similar rates of uptake and degradation, liver parenchymal cells did not take up the NC100150 Injection iron oxide particles. Light-microscopy methods did, however, indicate an increased iron load, presumably as ferritin/hemosiderin, within the hepatocytes 24 h post injection. The study also confirmed that compartmentalisation of ferritin/hemosiderin may cause a significant decrease in the MRI signal intensity of the liver. In conclusion, the combined results of this study imply that the prolonged presence of breakdown product in the liver may cause a prolonged imaging effect (in terms of signal loss) for a time period that significantly exceeds the half-life of NC100150 Injection iron oxide nanoparticles in liver.

Keywords
Animals, Cell Compartmentation/drug effects/physiology, Contrast Media/*metabolism/*pharmacokinetics, Endothelial Cells/drug effects/metabolism, Ferritin/metabolism, Hemosiderin/metabolism, Hepatocytes/drug effects/metabolism, Injections; Intravenous, Iron/*metabolism/*pharmacokinetics, Kupffer Cells/drug effects/metabolism, Liver/cytology/*drug effects/metabolism, Magnetic Resonance Imaging/methods, Male, Metabolic Clearance Rate/physiology, Oxides/*metabolism/*pharmacokinetics, Rats, Rats; Wistar, Time Factors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91938 (URN)10.1007/s00441-004-0884-8 (DOI)15103550 (PubMedID)
Available from: 2004-05-12 Created: 2004-05-12 Last updated: 2017-12-14Bibliographically approved
3. Long-term imaging effects in rat liver after a single injection of an iron oxide nanoparticle based MR contrast agent
Open this publication in new window or tab >>Long-term imaging effects in rat liver after a single injection of an iron oxide nanoparticle based MR contrast agent
2004 (English)In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 20, no 4, p. 622-631Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To investigate the duration of liver R2* enhancement and pharmacokinetics following administration of an iron oxide nanoparticle in a rat model.

MATERIALS AND METHODS: Rats were injected with 0, 1, 2, or 5 mg Fe/kg of NC100150 Injection, and quantitative in vivo 1/T2* liver measurements were obtained between 1 and 133 days after injection. The concentration of NC100150 Injection was determined by relaxometry methods in ex vivo rat liver homogenate.

RESULTS: At all dose levels, 1/T2* remained greater than control values up to 63 days after injection. In the highest dose group, 1/T2* was above control levels during the entire 133 day time-course investigated. There were no quantifiable amounts of NC100150 Injection present 63 days after injection in any of the dose groups. The half-life of NC100150 Injection in rat liver was dose dependent. For the lowest dose group, the degradation of the particles could be defined by a mono-exponential function with a half-life of eight days. For the 2 and 5 mg Fe/kg dose groups, the degradation was bi-exponential with a fast initial decay of seven to eight days followed by a slow terminal decay of 43-46 days.

CONCLUSION: NC100150 Injection exhibits prolonged 1/T2* enhancement in rat liver. The liver enhancement persisted at time points when the concentration of iron oxide particles present in the liver was below method detection limits. The prolonged 1/T2* enhancement is likely a result of the particle breakdown products and the induction of ferritin and hemosiderin with increasing iron cores/loading factors.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91939 (URN)10.1002/jmri.20175 (DOI)15390223 (PubMedID)
Available from: 2004-05-12 Created: 2004-05-12 Last updated: 2017-12-14Bibliographically approved
4. Temporal changes in liver R2* values of various superparamagnetic iron oxide contrast agents: Importance of hydrated particle size and coating material on the rat of liver clearance
Open this publication in new window or tab >>Temporal changes in liver R2* values of various superparamagnetic iron oxide contrast agents: Importance of hydrated particle size and coating material on the rat of liver clearance
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In: Invest RadiolArticle in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-91940 (URN)
Available from: 2004-05-12 Created: 2004-05-12Bibliographically approved

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